The goal of the proposed research is to develop a hybrid therapeutic peptide that induces both immediate and long-lasting protection against respiratory infection. The first portion of this hybrid is a bioactive mimetic of the C5a receptor. This bioactive peptide (EP67) specifically targets a limited subset of C5a receptor bearing cell populations in vivo. The targeted subset includes dendritic cells and excludes neutrophils. Binding of EP67 to the C5aR on dendritic cells induces APC activation and cytokine secretion. When EP67 is delivered directly to the lungs, it mediates emergency protection against respiratory viral infection. In the first aim of this project we will use influenza A as a model pathogen to explore this protection. The second portion of this hybrid therapeutic is the influenza A fusion peptide. The fusion peptide is the only region of hemagglutinin conserved throughout all mammalian influenza A families. Immunity to this peptide sequence could result in complete protection from all strains of mammalian influenza A. The second aim of the project will a panel of EP67-fusion loop hybrid peptide constructs for induction of immediate and long-term protection against serial influenza infection. The final aim of the proposal will study the mechanisms responsible for EP67 induced protection following targeted delivery to C5a receptor bearing cells in the lungs. To accomplish these goals, we have assembled a research team with expertise in immunology, protein chemistry, therapeutic delivery systems, age-related immunodeficiency, biological response modification, molecular biology, and biostatistics. Successful completion of these aims could revolutionize the clinical prevention and treatment of respiratory pathogens, replacing yearly vaccination with direct pulmonary delivery of a low cost hybrid peptide therapeutic that induces immediate, lifelong protection.